Rethinking animal models of sepsis - working towards improved clinical translation whilst integrating the 3Rs.

Sepsis is a major worldwide healthcare issue with unmet clinical need. Despite extensive animal research in this area, successful clinical translation has been largely unsuccessful. We propose one reason for this is that, sometimes, the experimental question is misdirected or unrealistic expectations are being made of the animal model. As sepsis models can lead to a rapid and substantial suffering - it is essential that we continually review experimental approaches and undertake a full harm:benefit impact assessment for each study. In some instances, this may require refinement of existing sepsis models. In other cases, it may be replacement to a different experimental system altogether, answering a mechanistic question whilst aligning with the principles of reduction, refinement and replacement (3Rs). We discuss making better use of patient data to identify potentially useful therapeutic targets which can subsequently be validated in preclinical systems. This may be achieved through greater use of construct validity models, from which mechanistic conclusions are drawn. We argue that such models could provide equally useful scientific data as face validity models, but with an improved 3Rs impact. Indeed, construct validity models may not require sepsis to be modelled, per se. We propose that approaches that could support and refine clinical translation of research findings, whilst reducing the overall welfare burden on research animals

Resveratrol Enhances Antitumor Activity of TRAIL in Prostate Cancer Xenografts through Activation of FOXO Transcription Factor

Resveratrol (3, 4', 5 tri-hydroxystilbene), a naturally occurring polyphenol, exhibits anti-inflammatory, antioxidant, cardioprotective and antitumor activities. We have recently shown that resveratrol can enhance the apoptosis-inducing potential of TRAIL in prostate cancer cells through multiple mechanisms in vitro. Therefore, the present study was designed to validate whether resveratrol can enhance the apoptosis-inducing potential of TRAIL in a xenograft model of prostate cancer.Resveratrol and TRAIL alone inhibited growth of PC-3 xenografts in nude mice by inhibiting tumor cell proliferation (PCNA and Ki67 staining) and inducing apoptosis (TUNEL staining). The combination of resveratrol and TRAIL was more effective in inhibiting tumor growth than single agent alone. In xenografted tumors, resveratrol upregulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and p27(/KIP1), and inhibited the expression of Bcl-2 and cyclin D1. Treatment of mice with resveratrol and TRAIL alone inhibited angiogenesis (as demonstrated by reduced number of blood vessels, and VEGF and VEGFR2 positive cells) and markers of metastasis (MMP-2 and MMP-9). The combination of resveratrol with TRAIL further inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells than single agent alone. Furthermore, resveratrol inhibited the cytoplasmic phosphorylation of FKHRL1 resulting in its enhanced activation as demonstrated by increased DNA binding activity.These data suggest that resveratrol can enhance the apoptosis-inducing potential of TRAIL by activating FKHRL1 and its target genes. The ability of resveratrol to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that resveratrol alone or in combination with TRAIL can be used for the management of prostate cancer

Factors associated with hospital readmission in sickle cell disease

<p>Abstract</p> <p>Background</p> <p>Sickle cell disease is the most frequent hereditary disease in Brazil, and people with the disease may be hospitalised several times in the course of their lives. The purpose of this study was to estimate the hazard ratios of factors associated with the time between hospital admissions.</p> <p>Methods</p> <p>The study sample comprised all patients admitted, from 2000 to 2004, to a university hospital in Rio de Janeiro State, south-east Brazil, as a result of acute complications from sickle cell disease (SCD). Considering the statistical problem of studying individuals with multiple events over time, the following extensions of Cox's proportional hazard ratio model were compared: the independent increment marginal model (Andersen-Gill) and the random effects model.</p> <p>Results</p> <p>The study considered 71 patients, who were admitted 223 times for acute events related to SCD. The hazard ratios for hospital readmission were statistically significant for the prior occurrence of vaso-occlusive crisis and development of renal failure. However, analysis of residuals of the marginal model revealed evidence of non-proportionality for some covariates.</p> <p>Conclusion</p> <p>the results from applying the two models were generally similar, indicating that the findings are not highly sensitive to different approaches. The better fit by the frailty model suggests that there are unmeasured individual factors with impact on hospital readmission.</p

Biofabrication of Anisotropic Gold Nanotriangles Using Extract of Endophytic Aspergillus clavatus as a Dual Functional Reductant and Stabilizer

Biosynthesis of metal and semiconductor nanoparticles using microorganisms has emerged as a more eco-friendly, simpler and reproducible alternative to the chemical synthesis, allowing the generation of rare forms such as nanotriangles and prisms. Here, we report the endophytic fungus Aspergillus clavatus, isolated from surface sterilized stem tissues of Azadirachta indica A. Juss., when incubated with an aqueous solution of chloroaurate ions produces a diverse mixture of intracellular gold nanoparticles (AuNPs), especially nanotriangles (GNT) in the size range from 20 to 35 nm. These structures (GNT) are of special interest since they possess distinct plasmonic features in the visible and IR regions, which equipped them with unique physical and optical properties exploitable in vital applications such as optics, electronics, catalysis and biomedicine. The reaction process was simple and convenient to handle and was monitored using ultraviolet–visible spectroscopy (UV–vis). The morphology and crystalline nature of the GNTs were determined from transmission electron microscopy (TEM), atomic force spectroscopy (AFM) and X-ray diffraction (XRD) spectroscopy. This proposed mechanistic principal might serve as a set of design rule for the synthesis of anisotropic nanostructures with desired architecture and can be amenable for the large scale commercial production and technical applications

Correlation Functions of Large N Chern-Simons-Matter Theories and Bosonization in Three Dimensions

We consider the conformal field theory of N complex massless scalars in 2+1 dimensions, coupled to a U(N) Chern-Simons theory at level k. This theory has a 't Hooft large N limit, keeping fixed \lambda = N/k. We compute some correlation functions in this theory exactly as a function of \lambda, in the large N (planar) limit. We show that the results match with the general predictions of Maldacena and Zhiboedov for the correlators of theories that have high-spin symmetries in the large N limit. It has been suggested in the past that this theory is dual (in the large N limit) to the Legendre transform of the theory of fermions coupled to a Chern-Simons gauge field, and our results allow us to find the precise mapping between the two theories. We find that in the large N limit the theory of N scalars coupled to a U(N)_k Chern-Simons theory is equivalent to the Legendre transform of the theory of k fermions coupled to a U(k)_N Chern-Simons theory, thus providing a bosonization of the latter theory. We conjecture that perhaps this duality is valid also for finite values of N and k, where on the fermionic side we should now have (for N_f flavors) a U(k)_{N-N_f/2} theory. Similar results hold for real scalars (fermions) coupled to the O(N)_k Chern-Simons theory.Comment: 49 pages, 16 figures. v2: added reference

Bio-nanotechnology application in wastewater treatment

The nanoparticles have received high interest in the field of medicine and water purification, however, the nanomaterials produced by chemical and physical methods are considered hazardous, expensive, and leave behind harmful substances to the environment. This chapter aimed to focus on green-synthesized nanoparticles and their medical applications. Moreover, the chapter highlighted the applicability of the metallic nanoparticles (MNPs) in the inactivation of microbial cells due to their high surface and small particle size. Modifying nanomaterials produced by green-methods is safe, inexpensive, and easy. Therefore, the control and modification of nanoparticles and their properties were also discussed

Resveratrol Induces Growth Arrest and Apoptosis through Activation of FOXO Transcription Factors in Prostate Cancer Cells

Resveratrol, a naturally occurring phytopolyphenol compound, has attracted extensive interest in recent years because of its diverse pharmacological characteristics. Although resveratrol possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. The present study was carried out to examine whether PI3K/AKT/FOXO pathway mediates the biological effects of resveratrol.Resveratrol inhibited the phosphorylation of PI3K, AKT and mTOR. Resveratrol, PI3K inhibitors (LY294002 and Wortmannin) and AKT inhibitor alone slightly induced apoptosis in LNCaP cells. These inhibitors further enhanced the apoptosis-inducing potential of resveratrol. Overexpression of wild-type PTEN slightly induced apoptosis. Wild type PTEN and PTEN-G129E enhanced resveratrol-induced apoptosis, whereas PTEN-G129R had no effect on proapoptotic effects of resveratrol. Furthermore, apoptosis-inducing potential of resveratrol was enhanced by dominant negative AKT, and inhibited by wild-type AKT and constitutively active AKT. Resveratrol has no effect on the expression of FKHR, FKHRL1 and AFX genes. The inhibition of FOXO phosphorylation by resveratrol resulted in its nuclear translocation, DNA binding and transcriptional activity. The inhibition of PI3K/AKT pathway induced FOXO transcriptional activity resulting in induction of Bim, TRAIL, p27/KIP1, DR4 and DR5, and inhibition of cyclin D1. Similarly, resveratrol-induced FOXO transcriptional activity was further enhanced when activation of PI3K/AKT pathway was blocked. Over-expression of phosphorylation deficient mutants of FOXO proteins (FOXO1-TM, FOXO3A-TM and FOXO4-TM) induced FOXO transcriptional activity, which was further enhanced by resveratrol. Inhibition of FOXO transcription factors by shRNA blocked resveratrol-induced upregulation of Bim, TRAIL, DR4, DR5, p27/KIP1 and apoptosis, and inhibition of cyclin D1 by resveratrol.These data suggest that FOXO transcription factors mediate anti-proliferative and pro-apoptotic effects of resveratrol, in part due to activation of extrinsic apoptosis pathway

The Formation of the First Massive Black Holes

Supermassive black holes (SMBHs) are common in local galactic nuclei, and SMBHs as massive as several billion solar masses already exist at redshift z=6. These earliest SMBHs may grow by the combination of radiation-pressure-limited accretion and mergers of stellar-mass seed BHs, left behind by the first generation of metal-free stars, or may be formed by more rapid direct collapse of gas in rare special environments where dense gas can accumulate without first fragmenting into stars. This chapter offers a review of these two competing scenarios, as well as some more exotic alternative ideas. It also briefly discusses how the different models may be distinguished in the future by observations with JWST, (e)LISA and other instruments.Comment: 47 pages with 306 references; this review is a chapter in "The First Galaxies - Theoretical Predictions and Observational Clues", Springer Astrophysics and Space Science Library, Eds. T. Wiklind, V. Bromm & B. Mobasher, in pres

Feeding Blueberry Diets in Early Life Prevent Senescence of Osteoblasts and Bone Loss in Ovariectomized Adult Female Rats

Appropriate nutrition during early development is essential for maximal bone mass accretion; however, linkage between early nutrition, childhood bone mass, peak bone mass in adulthood, and prevention of bone loss later in life has not been studied.In this report, we show that feeding a high quality diet supplemented with blueberries (BB) to pre-pubertal rats throughout development or only between postnatal day 20 (PND20) and PND34 prevented ovariectomy (OVX)-induced bone loss in adult life. This protective effect of BB is due to suppression of osteoblastic cell senescence associated with acute loss of myosin expression after OVX. Early exposure of pre-osteoblasts to serum from BB-fed rats was found to consistently increase myosin expression. This led to maintenance osteoblastic cell development and differentiation and delay of cellular entrance into senescence through regulation of the Runx2 gene. High bone turnover after OVX results in insufficient collagenous matrix support for new osteoblasts and their precursors to express myosin and other cytoskeletal elements required for osteoblast activity and differentiation.These results indicate: 1) a significant prevention of OVX-induced bone loss from adult rats can occur with only 14 days consumption of a BB-containing diet immediately prior to puberty; and 2) the molecular mechanisms underlying these effects involves increased myosin production which stimulates osteoblast differentiation and reduces mesenchymal stromal cell senescence